Exploring the TRAILs less travelled: TRAIL in cancer biology and therapy

Karstedt, Silvia von; Montinaro, Antonella; Walczak, Henning

doi:10.1038/nrc.2017.28

Cited by 473 publications

(492 citation statements)

References 185 publications

(271 reference statements)

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“…It has been published that the TRAIL C1595T variant changes in different points of multistage carcinogenesis, different cancer types and different ethnic groups in multistage carcinogenesis [21,38]. According to the results of our study, the lower frequency of TRAIL C1595T variant CT genotype in patients with NSCLC, although not statistically significant, suggests that this genotype appears to be a protective factor in terms of risk of lung cancer.…”

Section: Discussioncontrasting

confidence: 46%

Effect of trail C1595T variant and gene expression on the pathogenesis of non-small cell lung cancer

Erbasoglu

Horozoglu

Ercan

et al. 2018

Libyan Journal of Medicine

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It is known that disorders in apoptosis function play an important role in the pathogenesis of many types of cancer, including lung cancer. Tumor necrosis factor related apoptosis inducing ligand (TRAIL), a type II transmembrane protein, is a death ligand capable of inducing apoptosis by activating distinctive death receptor. Our purpose in this study is to investigate the gene polymorphisms in TRAIL molecular pathway and TRAIL gene expression levels in non-small cell lung cancer (NSCLC) patients in terms of pathogenesis and prognosis of the disease. In this study, TRAIL C1595T polymorphism was genotyped using polymerase chain reaction-restriction fragment length polymorphism analysis in 158 patients with NSCLC and 98 healthy individuals. Surgically resected tissues were examined and classified histopathologically. In addition, TRAIL gene expression levels in tumor tissue and tumor surrounding tissue samples of 48 patients with NSCLC were determined using real-time polymerase chain reaction. TRAIL gene expression levels of NSCLC patients were detected significantly 28.8 fold decrease in the tumor tissue group compared to the control group (p=0.026). When patients were compared to tumor stage, expression of TRAIL gene in advanced tumor stage was found to be significantly 7.86 fold higher than early tumor stage [p=0.028]. No significant relationship was found between NSCLC predisposition and prognostic parameters of NSCLC with TRAIL genotypes, but the frequency of TRAIL gene 1595 CT genotype was observed to be lower in the patients compared to the other genotypes, and the difference was found to be very close to statistical significance (p=0.07). It can be suggested that TRAIL may play an important role in the development of NSCLC and may be an effective prognostic factor in tumor progression.: It is known that disorders in apoptosis function play an important role in the pathogenesis of many types of cancer, including lung cancer. Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), a type II transmembrane protein, is a death ligand capable of inducing apoptosis by activating distinctive death receptor. Our purpose in this study is to investigate the gene polymorphisms in TRAIL molecular pathway and TRAIL gene expression levels in non-small cell lung cancer (NSCLC) patients in terms of pathogenesis and prognosis of the disease.

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Section: Discussioncontrasting

confidence: 46%

Effect of trail C1595T variant and gene expression on the pathogenesis of non-small cell lung cancer

Erbasoglu

Horozoglu

Ercan

et al. 2018

Libyan Journal of Medicine

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“…Therefore, to determine the therapeutic potential of TRAIL, it is necessary to identify the potential indicators of TRAIL efficacy and analyze the molecular mechanisms of TRAIL resistance in various cancer cells. Therefore, we evaluated the efficacy of CGs through ROS generation and autophagy, thereby evaluating the sensitizing mechanisms of hepatocellular carcinoma cells to TRAIL …”

Section: Discussionmentioning

confidence: 99%

“…This complex merges with adaptor molecules, such as Fas‐associated death domain (FADD) and caspase‐8, thereby resulting in the formation of caspase‐9 and subsequent activation of caspase‐3. These mechanisms are known for inducing extrinsic or death receptor‐mediated apoptotic cell death . The intrinsic or Bcl‐2‐regulated pathway is consequently regulated by members of the Bcl‐2 family after external stimuli from chemotherapeutic agents.…”

Section: Introductionmentioning

confidence: 99%

Cardiac glycoside sensitized hepatocellular carcinoma cells to TRAIL via ROS generation, p38MAPK, mitochondrial transition, and autophagy mediation

Rasheduzzaman

Yin

Park

2019

Molecular Carcinogenesis

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A major concern in the clinical application of tumor necrosis factor related apoptosis‐inducing ligand (TRAIL) in tumors is the development of resistance. Therefore, agents that can potentially restore TRAIL sensitivity are important therapeutic targets for cancer treatment. Herein, we evaluated lanatoside c and digoxin, both of which are widely used cardiac glycosides (CGs), for their ability to sensitize human hepatocellular carcinoma cells (Huh‐7 and HepG2) through TRAIL‐induced apoptosis. CGs functionalize TRAIL as shown by its effect on intracellular reactive oxygen species (ROS) generation, which damages mitochondrial integrity and thereby confers intrinsic apoptotic caspase cascade during combined treatment. Caspase activation is dependent on ROS as shown by the ability of CGs to generate ROS and the ROS‐N‐acetylcysteine (NAC) relationship, which inhibits apoptosis during cotreatment by preventing the formation of caspase‐8 and ‐3. Furthermore, CGs triggered p38MAPK phosphorylation and NAC pre‐exposure blocked p38MAPK phosphorylation, which demonstrated that p38MAPK was dependent upon ROS generation. Additionally, CGs were found to be potent inducers of AMPK‐mediated protective autophagy as pharmacological and genetic autophagy inhibition reached the higher threshold of TRAIL‐mediated apoptosis. Finally, CGs downregulated the expression of the antiapoptotic protein Bcl‐2 and increased the translocation of proapoptotic protein cytochrome c, thereby inducing apoptosis. Collectively, these results indicate that CGs potentiate the enhanced cytotoxic capacity to TRAIL through ROS generation, p38MAPK phosphorylation, cell survival protein downregulation, and protective autophagy inhibition.

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“…5b), and inflammatory signalling and necroptosis are thought to be mediated by the formation of a secondary cytosolic receptor complex II (REF. 177). Recent studies indicate that RIPK1 (REFS 178,179) and LUBAC 179 can be directly recruited to membrane-bound TRAILR, suggesting that NF-κB activation can occur at the plasma membrane.…”

Section: Cell Death Regulation By Ubiquitin Ligasesmentioning

confidence: 99%

“…Understanding the signalling circuits that are activated downstream of TRAILR is of special interest, as several TRAILR agonists have been evaluated as putative cancer therapeutics with limited clinical success (reviewed in REF. 177). The finding that TRAILR can induce migratory 180 and inflammatory responses that promote tumorigenesis 181 sheds light on the complex signalling circuits that respond to TRAIL.…”

Section: Cell Death Regulation By Ubiquitin Ligasesmentioning

confidence: 99%

Ubiquitin ligases in oncogenic transformation and cancer therapy

2017

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The cellular response to external stress signals and DNA damage depends on the activity of ubiquitin ligases (E3s), which regulate numerous cellular processes, including homeostasis, metabolism and cell cycle progression. E3s recognize, interact with and ubiquitylate protein substrates in a temporally and spatially regulated manner. The topology of the ubiquitin chains dictates the fate of the substrates, marking them for recognition and degradation by the proteasome or altering their subcellular localization or assembly into functional complexes. Both genetic and epigenetic alterations account for the deregulation of E3s in cancer. Consequently, the stability and/or activity of E3 substrates are also altered, in some cases leading to downregulation of tumour-suppressor activities and upregulation of oncogenic activities. A better understanding of the mechanisms underlying E3 regulation and function in tumorigenesis is expected to identify novel prognostic markers and to enable the development of the next generation of anticancer therapies. This Review summarizes the oncogenic and tumour-suppressor roles of selected E3s and highlights novel opportunities for therapeutic intervention.

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Exploring the TRAILs less travelled: TRAIL in cancer biology and therapy

Cited by 473 publications

References 185 publications

Effect of trail C1595T variant and gene expression on the pathogenesis of non-small cell lung cancer

Effect of trail C1595T variant and gene expression on the pathogenesis of non-small cell lung cancer

Cardiac glycoside sensitized hepatocellular carcinoma cells to TRAIL via ROS generation, p38MAPK, mitochondrial transition, and autophagy mediation

Ubiquitin ligases in oncogenic transformation and cancer therapy

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